PROPOSAL SUMMARY/ABSTRACT Sustained attention ? the continuous allocation of cognitive resources to respond to infrequent but behaviorally relevant stimuli ? is impaired in many psychiatric disorders and represents an important aspect of cognitive control. Sustained attention requires top-down control and engagement with the external world, which is linked to both frontoparietal and thalamic controlling signals on primary sensor cortices. Despite the extensive behavioral characterization of sustained attention in animal models using the five-choice serial reaction time task (5-CSRTT), very little is known about the oscillatory interaction between the dorsal attention network and thalamo-cortical dynamics and its potential as a stimulation target for enhancing sustained attention. The objective of this project is to dissect the causal role of higher-order thalamo-cortical oscillations in sustained attention via temporally-precise rhythmic stimulation. I will focus on three regions in the visual thalamo-cortical network: higher-order visual thalamus (lateral aspect of lateral posterior nucleus, LPl), posterior parietal cortex (PPC), and primary visual cortex (V1). I will test the central hypothesis that LPl-cortical theta (4-7 Hz) functional connectivity causally coordinates PPC-V1 functional connectivity to facilitate sustained attention. The rationale of this work is that the proposed temporally-precise rhythmic optogenetic perturbations will directly test the causal role of thalamo-cortical functional connectivity in sustained attention. Accordingly, the two specific aims are: (1) Delineate the functional role of higher-order thalamo-cortical oscillations in sustained attention, (2) Determine the causal role of thalamo-cortical functional connectivity in sustained attention via temporally-precise rhythmic optogenetics. This work is significant because it will causally test a convergent model in which higher-order visual thalamus coordinates the parietal top-down control signals onto visual cortex that is crucial for developing circuit- based therapies to enhance sustained attention. The work is innovative due to its integration of closed-loop optogenetics circuit interrogation, multisite electrophysiology, freely-moving sustained attention task, and machine-learning tools for the investigation of the causal role of oscillatory synchronization. The overall positive impact of the proposed study is to provide a more comprehensive map of how the higher-order visual thalamus interacts with the frontoparietal control signal to modulate V1, and thus mediates sustained attention, a transdiagnostic cognitive function that shows impairment in many psychiatric disorders including attention deficit hyperactivity disorder, bipolar disorder, and schizophrenia. The implication of this study is that it may reveal a general mechanism underlying the interaction between two higher-order processing structures signaling to lower sensory cortices during cognitive processing.